Dataset Information

Prognostic Risk Model and Tumor Immune Environment Modulation of m5C-Related LncRNAs in Pancreatic Ductal Adenocarcinoma.

ABSTRACT: RNA methylation modification is a key process in epigenetics that regulates posttranscriptional gene expression. With advances in next-generation sequencing technology, 5-methylcytosine (m5C) modification has also been found in multiple RNAs. Long non-coding RNAs (lncRNAs) were proved to have a key role in cancer progression and closely related to the tumor immune microenvironment. Thus, based on the PDAC patients' clinical information and genetic transcriptome data from the TCGA database, we performed a detailed bioinformatic analysis to establish a m5C-related lncRNA prognostic risk model for PDAC patients and discovered the relationship between the risk model and PDAC immune microenvironment. Pearson correlation coefficient analysis was applied to conduct a m5C regulatory gene and m5C-related lncRNA co-expression network. Expression of m5C-related lncRNAs screened by univariate regression analysis with prognostic value showed a significant difference between pancreatic cancer and normal tissues. The least absolute shrinkage and selection operator (LASSO) Cox regression method was applied to determine an 8-m5C-related lncRNA prognostic risk model. We used principal component analysis to indicate that the risk model could distinguish all the samples clearly. The clinical nomogram also accurately predicted 1-, 1.5-, 2-, and 3-year survival time among PDAC patients. Additionally, this risk model was validated in the entire group and sub-test groups using KM analysis and ROC analysis. Combined with the clinical characteristics, the risk score was found to be an independent factor for predicting the survival of PDAC patients. Furthermore, the association between the risk model and tumor immune microenvironment was evaluated via the ESTIMATE R package and CIBERSORT method. Consequently, the results indicated that immune cells were associated with m5C-related lncRNA risk model scores and had different distribution in the high- and low-risk groups. Based on all these analyses, the m5C-related lncRNA risk model could be a reliable prognostic tool and therapeutic target for PDAC patients.

SUBMITTER: Yuan H

PROVIDER: S-EPMC8692582 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundNeoadjuvant folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) and chemoradiation have been used to downstage borderline and locally advanced pancreatic ductal adenocarcinoma (PDAC). Whether neoadjuvant therapy-induced tumor immune response contributes to the improved survival is unknown. Therefore, we evaluated whether neoadjuvant therapy induces an immune response towards PDAC.MethodsClinicopathological variables were collected for surgically resected PDACs at the Massachusetts General Hospital (1998-2016). Neoadjuvant regimens included FOLFIRINOX with or without chemoradiation, proton chemoradiation (25 Gy), photon chemoradiation (50.4 Gy), or no neoadjuvant therapy. Human leukocyte antigen (HLA) class I and II expression and immune cell infiltration (CD4+, FoxP3+, CD8+, granzyme B+ cells, and M2 macrophages) were analyzed immunohistochemically and correlated with clinicopathologic variables. The antitumor immune response was compared among neoadjuvant therapy regimens. All statistical tests were 2-sided.ResultsTwo hundred forty-eight PDAC patients were included. The median age was 64 years and 50.0% were female. HLA-A defects were less frequent in the FOLFIRINOX cohort (P = .006). HLA class II expression was lowest in photon and highest in proton patients (P = .02). The FOLFIRINOX cohort exhibited the densest CD8+ cell infiltration (P < .001). FOLFIRINOX and proton patients had the highest CD4+ and lowest T regulatory (FoxP3+) cell density, respectively. M2 macrophage density was statistically significantly higher in the treatment-naïve group (P < .001) in which dense M2 macrophage infiltration was an independent predictor of poor overall survival.ConclusionsNeoadjuvant FOLFIRINOX with or without chemoradiation may induce immunologically relevant changes in the tumor microenvironment. It may reduce HLA-A defects, increase CD8+ cell density, and decrease T regulatory cell and M2 macrophage density. Therefore, neoadjuvant FOLFIRINOX therapy may benefit from combinations with checkpoint inhibitors, which can enhance patients' antitumor immune response.

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive, fatal tumor. N6-methylandenosine (m6A) methylation is the major epigenetic modification of RNA including lncRNAs. The roles of m6A-related lncRNAs in PDAC have not been fully clarified. This study aims to assess gene signatures and prognostic value of m6A-related lncRNAs in PDAC. The Cancer Genome Atlas (TCGA) dataset and the International Cancer Genome Consortium (ICGC) dataset were explored to identify m6A-related lncRNAs. Univariate, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression were performed to construct the m6A-related lncRNAs prognostic riskscore (m6A-LPR) model to predict the overall survival (OS) in the TCGA training cohort. Kaplan-Meier curve with log-rank test and receiver operating characteristic (ROC) curve were used to evaluate the prognostic value of the m6A-LPR. Furthermore, the robustness of the m6A-LPR was further validated in the ICGC cohort. Tumor immunity was evaluated using ESTIMATE and CIBERSORT algorithms. A total of 262 m6A-related lncRNAs were identified in two datasets. In the TCGA training cohort, 28 prognostic m6A-related lncRNAs were identified and the m6A-LPR including four m6A-related lncRNAs was constructed. The m6A-LPR was able to identify high-risk patients with significantly poorer OS and accurately predict OS in both the TCGA training cohort and the ICGC validation cohort. Analysis of tumor immunity revealed that high-risk groups had remarkably lower stromal, immune, and ESTIMATE scores. Moreover, high-risk groups were associated with significantly higher levels of plasma B cells and resting NK cells infiltration, and lower levels of infiltrating resting memory CD4 T cells, monocytes, and resting mast cells. Our study proposed a robust m6A-related prognostic signature of lncRNAs for predicting OS in PDAC, which provides some clues for further studies focusing on the mechanism process underlying m6A modification of lncRNAs.

Dataset Information

Prognostic Risk Model and Tumor Immune Environment Modulation of m5C-Related LncRNAs in Pancreatic Ductal Adenocarcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets